Cutting Edge: Conditional MHC Class II Expression Reveals a Limited Role for B Cell Antigen Presentation in Primary and Secondary CD4 T Cell Responses

Abstract

The activation, differentiation and subsequent effector functions of CD4 T cells depend on interactions with a multitude of MHCII-expressing antigen presenting cells (APCs). To evaluate the individual contribution of various APCs to CD4 T cell function, we have designed a new murine tool for selective in vivo expression of MHCII in subsets of APCs. Conditional expression of MHCII in B cells was achieved using a cre-loxP approach. After intravenous or subcutaneous priming, partial proliferation and activation of CD4 T cells was observed in mice expressing MHCII only by B cells. Restricting MHCII expression to B cells constrained secondary CD4 T cell responses in vivo, as demonstrated in a CD4 T cell-dependent model of autoimmunity, EAE. These results highlight the limitations of B cell antigen presentation during initiation and propagation of CD4 T cell function in vivo using a novel system to study individual APCs by the conditional expression of MHCII.

B cell antigen presentation is sufficient to drive neuro-inflammation in an animal model of multiple sclerosis

“…B MHCII mice were generated as previously reported (25). DC MHCII mice (26) were kindly provided by Dr. Terri Laufer (University of Pennsylvania).…”

“…However, B cell MHCII expression alone is not sufficient to support active or passive EAE (25). Thus, we sought to determine the basis of resistance to EAE in B MHCII mice, in which B cells exclusively express MHCII (25). Because cognate B and T cell interactions have been implicated during pathogenic CD4 T cell-dependent responses, including autoimmune CNS demyelination (14, 21), we reasoned that elevating the efficiency with which APCs acquire and present antigen to CD4 T cells would facilitate disease.…”

“…Based on these results, along with the results of B cell depletion studies in MS and EAE, we hypothesized that B cell antigen presentation cooperates with DC antigen presentation to maximize the initial response to rMOG protein during active EAE induction. To explore the possible cooperation between DC and B cell antigen presentation during the initiation of EAE, we bred mice in which MHCII expression is restricted to DCs (DC MHCII (26)) to those in which MHCII expression is restricted to B cells (B MHCII (25)), generating mice in which DCs and B cells are the only MHCII-bearing cells (DC MHCII xB MHCII ). After thymic grafting from B6 neonates, mice were immunized with rMOG according to standard protocols (6).…”

“…Active and passive EAE were induced according to prior reports (25,28). Briefly, active EAE was induced in mice by subcutaneous injection of 200 μg MOG emulsified in complete Freund's adjuvant (CFA; Sigma) containing 500 μg H37RA (Difco, Detroit, MI) and intraperitoneal (i.p.)…”

“…Alternatively, mice were injected with 150 μg rMOG protein (residues 1-125 of human MOG protein (6)) in 500 μg CFA. Passive EAE was established by transfer of 1×10 7 MOGspecific, Thy1.1+ encephalitogenic cells as reported (25,29). Mice were observed daily and clinical score were assessed with a five point scoring system, as follows: 0 = no disease; 1 = limp tail; 2 = mild hind limb paresis; 3 = severe hind limb paresis; 4 = complete hind limb plegia or quadriplegia; 5 = moribund or dead.…”